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adults.6,9 The most common histologic subtypes of melanoma occurring in children are supercial spreading melanoma and nodular melanoma.7,11 RISK FACTORS The risk of melanoma is increased in children with giant congenital melanocytic nevi, dysplastic nevus syndrome, xeroderma pigmentosum, or immunodeciency states. Increased numbers of benign nevi, the inability to tan, and a history of blistering sunburns during childhood and adolescence confer greater susceptibility to the development of melanoma in adult life.12 However, the relevance of such factors to the development of childhood melanoma is unknown. SYMPTOMS OF MELANOMA IN CHILDREN Melanoma may be congenital or may develop in infancy either alone or in association with a preexisting nevus, including the giant congenital melanocytic nevus.13 Detecting the latter at an early stage is difcult because malignant transformation commonly evolves in the deeper components of a congenital nevus, and surface alterations are a late manifestation. Changes in a long-standing pigmented lesion, such as bleeding after minor trauma, inammation, and increasing size or swelling, are sometimes overlooked or erroneously ascribed to other factors. Decreased survival has been attributed in up to 60 percent of cases to delays in diagnosis, most commonly due to the physicians hesitancy to recognize melanoma in children.14 The clinical ndings that indicate melanoma in children are large or expanding size, irregular borders and pigment distribution, and surface changes such as ulceration and loss of skin markings.5 Melanoma may be associated with clinical symptoms such as pain or pruritus. Whereas Spitz nevi are usually under 1 cm in diameter and may resemble verrucae or small hemangiomas, melanomas in children tend to be larger and quite striking clinically (Fig. 1A and 1B). Melanoma may also present as a subcutaneous mass beneath a pigmented lesion or as regional lymphadenopathy.
AND

MELANOMA IN CHILDREN PATRICIA I. CEBALLOS, M.D., RAMON RUIZ-MALDONADO, M.D., AND M ARTIN C. M IHM , J R ., M.D.

O give a child the ominous diagnosis of malignant melanoma is a very difcult decision for both clinician and pathologist. Difculties in histologic diagnosis combined with a reluctance on the part of the clinician may lead to delays in diagnosis and curative surgical intervention. In fact, some melanomas in children are misdiagnosed clinically as benign lesions and recognized as melanomas only after excision. It is imperative to recognize that malignant melanoma occurs in children and to appreciate its clinical characteristics and predisposing factors. INCIDENCE AND PROGNOSIS Approximately 2 percent of melanomas occur in patients under the age of 20 years, and 0.3 to 0.4 percent of melanomas occur in prepubertal children.1 Before the Spitz nevus became recognized as a separate entity, the prognosis of melanoma in childhood was considered to be relatively favorable.2 Spitz nevi were frequently misdiagnosed as melanomas,2 and the course of the nevi is benign. Malignant melanoma in childhood can metastasize and may follow an aggressive course. With metastatic disease, ve-year survival rates are in the range of 33 to 34 percent.3,4 Eighty percent of children with melanoma present with stage I disease.5,6 Rates of disease-free survival in children are comparable to those in adults with stage I or II disease: approximately 77 percent at ve years.7 The thickness of the melanoma and the level of invasion are the most important predictors of long-term survival.8,9 Nodal metastases develop in up to two thirds of children with deeply invasive melanomas (Clarks levels IV and V) or with melanomas more than 1.5 mm thick.9,10 Conversely, metastases or recurrent tumors are unusual in patients with lesions less than 1.5 mm thick.9 Twenty percent of melanomas in children and adolescents occur in the head and neck, the remainder being distributed equally on the trunk and extremities.6 In children, the time to recurrent disease is shorter (6.2 years) than in adults (8.4 years).6,8 Furthermore, some studies show that melanomas in children tend to be thicker overall (1.5 mm) than is known to be true for
From the Department of Dermatology, Dermatopathology Section, New York University Medical Center, New York (P.I.C.); the National Institute of Pediatrics, Mexico City, Mexico (R.R.-M.); and the Department of Dermatology and Dermatopathology, Albany Medical College, Albany, N.Y. (M.C.M.). Address reprint requests to Dr. Mihm at Albany Medical College, 47 New Scotland Ave., Suite K213, Albany, NY 12208-3479.

ORIGIN, SIGNS,

CONGENITAL MELANOMA Melanomas that develop in utero are rare, and most arise in melanocytic nevi.15-17 Other congenital melanomas are acquired transplacentally.14 Melanomas account for only 8 percent of the cancers that affect pregnant women but for 46 percent of fetal tumors acquired transplacentally.18-22 Neonates with acquired melanoma usually have multiorgan involvement. Cutaneous involvement takes the form of small blue-black macules or nodules, or large, rm, palpable masses. Microscopically, there are subepidermal aggregates of melanoma cells with variable epidermotropism. Although infants with transplacentally acquired melanoma usually do poorly, spontaneous complete regression has been described.21,22 Congenital melanoma may arise in association with a large or giant congenital nevus. It commonly develops

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Figure 1. Primary Malignant Melanomas in Two Children. Shown are a primary malignant melanoma arising in a congenital nevus on the chest of a six-month-old child (Panel A; courtesy of Dr. G. Ibarra-Duran, Mexico) and a primary nodular malignant melanoma on the back of a fair-skinned 14-year-old boy, arising in sun-damaged skin (Panel B).

in the deeper aspects of the nevus and may be problematic histologically. Sometimes numerous cutaneous satellite lesions, which may be widely disseminated, are present at birth (Fig. 2). Nodal metastases and visceral involvement should be ruled out. Primary cutaneous congenital melanomas tend to be smaller, between 1 and 3 cm, and may grow rapidly, ulcerate, and bleed. These signs in any pigmented lesion in a newborn should prompt excisional biopsy without delay. The biologic behavior of congenital melanomas is especially unpredictable. The presence or absence of metastases in regional lymph nodes does not correlate consistently with survival.23,24 MELANOMA ARISING IN CONGENITAL NEVI Congenital nevi are often larger than nevi that appear later in life (acquired melanocytic nevi).25 Large congenital nevi occur in 1 in 1000 to 1 in 20,000 newborns.26 Small congenital nevi (usually 1 or 2 cm in greatest diameter) are much more common, with a 1 percent incidence in newborn children.27 Garment

nevi involve a very large body-surface area for example, the entire back or an extremity and occur in 1 in 500,000 newborns. At least one third of prepubertal melanomas arise in large congenital nevi.3 The frequency of malignant transformation in congenital nevi has been estimated to be between 2 and 20 percent, although an incidence of 5 percent was reported in a prospectively followed series of 80 children (Fig. 1A).26,28 Rarely, other neuroectodermal neoplasms develop in congenital nevi (Fig. 3). Half the cases of melanoma within large congenital nevi occur in the rst decade of life.28,29 The risk of melanoma arising in a large congenital nevus during the rst year of life (8.6 per 10,000) exceeds the risk associated with general anesthesia (1.2 per 10,000).29 Accordingly, some authors recommend prophylactic removal of large congenital melanocytic nevi in early life,30 citing excellent cosmetic results, the removal of a potential melanoma precursor, and possible psychological benets. Because as many as two thirds of melanomas evolv-

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normal skin, offspring may manifest the dysplastic nevus phenotype by early adolescence.34 An important clue to the dysplastic nevus syndrome in children is the presence of abundant normal-looking nevi by the age of ve or six years. During puberty the dysplastic nevus phenotype becomes fully expressed, perhaps under the inuence of such inducers as solar radiation, hormones, and altered host immunity.35 Dysplastic nevi can also occur in prepubertal children.11,33 The scalp is often the rst site of involvement and must be examined. In addition, dysplastic nevi commonly affect the horse collar area of the torso and the buttocks (Fig. 4A). An inverse pattern with predominant involvement of the extremities is also known to occur. Dysplastic nevi tend to be larger than common acquired nevi, with diameters between 5 and 10 mm. They typically have fuzzy, indistinct borders and are multicolored in shades of tan, brown, pink, and black. They vary from macular forms to papules sur-

Figure 2. A 10-Day-Old Boy with a Giant Garment Congenital Nevus and Disseminated Cutaneous Melanoma Metastases. The patient died of metastatic melanoma.

ing in large congenital nevi have nonepidermal origins, prophylactic removal of such lesions should extend to muscle fascia, with partial excision of muscle if nevic nests remain.27 With giant garment nevi, lifelong clinical surveillance at frequent intervals is recommended by most authorities. Neurocutaneous melanosis is a rare entity associated with the presence of a large congenital nevus on the scalp or upper back, with intracerebral nevic proliferation, which can lead to hydrocephalus and seizures. Leptomeningeal melanoma may develop.31,32 DYSPLASTIC NEVUS SYNDROME Dysplastic nevi are potential precursors of malignant melanoma. Cutaneous melanoma in persons with dysplastic nevi usually develops within melanocytic dysplasias, although melanoma may also arise in unaffected skin. In children with dysplastic nevi, melanoma has been documented as early as the age of 10 years; as in adults, it is usually the supercial spreading variant.33 In melanoma-prone kindreds in which one of the parents has a history of melanoma but otherwise has

Figure 3. Neuroblastoma Presenting as a Large Mass within a Giant Garment Congenital Nevus. The widely disseminated pigmented patches represent satellite melanocytic nevi. The patient died of metastatic neuroblastoma.28

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B Figure 4. Dysplastic Nevi. Panel A shows a young boy with a characteristic pattern of dysplastic nevi on the torso. Dysplastic nevi tend to be multiple and appear slightly larger and more irregular than the common small melanocytic nevi appearing in childhood. Panel B shows a characteristic dysplastic nevus with a central hyperpigmented papule, surrounded by a lighter macular component with slightly irregular borders (courtesy of the Ronald O. Perelman Department of Dermatology, New York University Medical Center).

rounded by a lighter macular component (Fig. 4B). The persistence of a macular component in a nevus larger than 6 mm is strong evidence of dysplasia.34 The appearance of a new area of black pigmentation in a dysplastic nevus may be the best indicator of early malignant change.35 There are no established guidelines for clinical follow-up in affected children. Annual skin examinations by a dermatologist, with periodic photographic documentation, are probably sufcient for a child with stable lesions. Children with multiple dysplastic nevi that show evidence of change, as well as those with a personal or family history of melanoma, should be examined at more frequent intervals. Regular use of sunscreen and avoidance of intense sun exposure should be advised. XERODERMA PIGMENTOSUM Xeroderma pigmentosum is a rare inherited disorder characterized by photosensitivity and defective cellular repair of DNA damaged by ultraviolet radiation. Skin cancer develops in affected children at an alarming rate (Fig. 5). Melanoma develops in 5 percent of these patients, at a median age of 19 years, usually on the head

or neck.36 Children with xeroderma pigmentosum must be monitored very closely and evaluated at frequent intervals. Protective clothing and regular use of sunscreen are imperative. IMMUNOSUPPRESSION Host immunity plays an important part in the biologic behavior of melanoma. Children with genetically determined immunodeciencies have a three- to sixfold risk of melanoma.37 Melanocytic dysplasias may arise in children who are treated with immunosuppressive medications or are infected with the human immunodeciency virus.38,39 Because of the possibility of accelerated progression of melanocytic dysplasias to melanoma in immunocompromised hosts, we advocate a more aggressive approach to the management of dysplastic nevi in such patients. Prophylactic removal of such lesions, unless they are too numerous, is prudent. SPITZ NEVUS The Spitz nevus may have a benign clinical appearance, yet the histologic features can be alarming. Spitz nevi are more common in children than in adults and preferentially involve the head and neck.40 They are al-

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most always less than 1 cm across, dome-shaped, and pink-tan in color. A Spitz nevus often resembles a verruca or a hemangioma (Fig. 6). Microscopically, Spitz nevi share many features with melanomas. In childhood these lesions tend to appear even more ominous because of the frequent nding of pagetoid growth and a high mitotic rate in the supercial aspects of the lesion. Histologic attributes that strongly indicate melanoma as opposed to Spitz nevus are a lack of maturation, mitoses in the deeper portion, marked nuclear pleomorphism and hyperchromasia, and an expansile architecture in the dermis. Ancillary techniques such as ow cytometry and silver staining of nucleolar-organizer regions have been explored in an attempt to improve the histologic differentiation of these entities. Unfortunately, Spitz nevi may be aneuploid and some melanomas are diploid in DNA content, rendering ow cytometry an impractical tool. Silver staining of nucleolar-organizer regions has been similarly unhelpful. Cases of metastasizing Spitz nevi have been de-

Figure 6. Spitz Nevus on the Auricle of a Young Child. The lesion is a dome-shaped, pink-red papule. Spitz nevi are frequently nonpigmented (courtesy of the Ronald O. Perelman Department of Dermatology, New York University Medical Center).

scribed, in which metastases were conned to regional lymph nodes and patients had an excellent prognosis after considerable follow-up.41 These cases, as well as some cases of childhood melanoma that behave unpredictably, attest to the limitations of current diagnostic techniques. MALIGNANT BLUE NEVUS Although it is usually seen in adults,42 the malignant blue nevus has also been documented in young children. It preferentially involves the scalp and presents usually as a multinodular plaque at least 2 cm in diameter, with a history of progressive enlargement of a long-standing dark-blue-to-black lesion. In metastatic malignant blue nevus, which can be fatal, the deposits show atypical cytologic features, increased mitoses, pleomorphism, and necrosis.42 Although this tumor may arise independently, it is more commonly associated with a precursor cellular blue nevus. Cellular blue nevi may generate benign metastases to regional lymph nodes in approximately 5.2 percent of cases.42 However,

Figure 5. Eight-Year-Old Boy with Xeroderma Pigmentosum and a Destructive Basal-Cell Carcinoma on the Nose. The sun-exposed skin appears badly sun-damaged and prematurely aged.

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such metastases exhibit histologic delity to the primary lesion that is, they are cytologically benign. The rate of malignant transformation of cellular blue nevi is unknown.42 THERAPY We strongly recommend that suspicious pigmented lesions undergo excisional biopsy whenever possible. This is crucial, because excisional biopsy permits microscopical evaluation of the entire lesion, including its deepest portion. Furthermore, this approach allows detection of satellite lesions, vascular invasion, and in-transit metastases. We recommend incisional or punch biopsy only when excision is precluded by the size or location of the lesion. In this case, we recommend selective biopsy of elevated areas or, in at lesions, of the darkest areas. Once the diagnosis of melanoma has been established, denitive surgical excision should be performed. The World Health Organization currently advocates an excision margin of 1.0 cm for melanomas 1.0 mm thick or less.43 Melanomas thicker than 1.0 mm should be excised with wider margins, ranging from 1.5 to 3.0 cm depending on lesional depth.44 Reexcision with margins greater than 3 cm is no longer recommended, since it offers no survival advantage. Primary closure should be performed if possible. Modern tissue-expansion techniques, combined with the revised narrower margins of excision, permit primary closure (as opposed to skin grafting) in most children. Lymph-node dissection should be performed if draining regional nodes are suspiciously enlarged. Therapy for children with advanced disease is the same as for adults, with some exceptions in very young infants. The ability of interleukin-2 to expand T cells with antitumor reactivity has therapeutic applications. Immunotherapy using interleukin-2 with or without lymphokine-activated killer cells may induce partial or complete remissions in adults with metastatic melanoma, with a combined response rate of 23 percent.45 However, relapses are the rule rather than the exception. Therapy with constant infusion of interleukin-2 alone has caused partial responses in adults with less toxicity.46 The use of interleukin-2 in children over six months of age is under preliminary investigation.47 Adoptive immunotherapy with tumor-inltrating lymphocytes is a promising therapeutic weapon against melanoma as well as other cancers because of the capacity of these cells to recognize specic tumor antigens restricted by the major histocompatibility complex (MHC). The administration of harvested tumor-inltrating lymphocytes in combination with interleukin-2 and cyclophosphamide (or irradiation) has been studied.48,49 The up-regulation of class I MHC antigens in tumor cells by interferon gamma or the introduction of the gene coding for class I antigen into tumor cells enhances the effectiveness of tumor-inltrating lym-

phocytes.49 In addition, the synergistic role of cyclophosphamide is probably due to reduction of the tumor mass or an increase in local lymphocytic inammation. In one study, 38 percent of adult patients had responses to immunotherapy with tumor-inltrating lymphocytes.49 Cancer therapy with genetic modication, such as retrovirus-mediated transduction of genes into humans, is also feasible. The tumor necrosis factor gene has been inserted into tumor-inltrating lymphocytes, which were subsequently administered to patients with advanced melanoma. These genetically modied tumorinltrating lymphocytes can be added to the list of immunotherapeutic tools under investigation.48 Most reported studies of melanoma therapy exclude children under 11 or 12 years of age. Various chemotherapy regimens have been evaluated, including limb perfusion with melphalan in adolescents with level IV or V melanomas on the extremities ranging from 1 to 15 mm thick.50 Some of the patients had regional-node metastases. The ve-year survival rate with this protocol was 93 percent. Furthermore, all the patients with lesions more than 3 mm thick and stage I disease had excellent disease-free survival.50 Intensive melphalan or carmustine therapy, combined with autologous bone marrow transplantation in adults with refractory melanoma, yielded 69 percent and 37 percent response rates, respectively,51,52 but this approach to treatment has not yet been reported in children. Chemotherapy with dacarbazine was successful in four children with high-risk melanomas and evidence of disseminated disease.53 Dacarbazine has thus far been the most effective single chemotherapeutic agent for metastatic melanoma in adults, with response rates between 15 and 25 percent (including partial and complete responses) and survival periods of several months.54 Combination treatments with alpha interferons and dacarbazine are associated with greater overall response rates (53 percent) than are treatments in which either agent is administered singly (approximately 20 percent).54-56 Forty percent of adult patients had complete responses with combination therapy, as compared with 2 to 5 percent with single-agent dacarbazine treatment.54 However, the overall response to treatment is closely related to the presence of soft-tissue and nodal metastases as opposed to visceral and skeletal metastases. Whereas combinations of chemotherapeutic drugs do not improve response or survival statistics in adults, the study by Hayes and Green suggests that children with metastatic melanoma may be more responsive to such treatment as a triple-drug regimen of cyclophosphamide, vincristine, and dactinomycin.57 Despite encouraging results, there is as yet no truly effective therapy for metastatic melanoma in adults or children. Consequently, the importance of early diagnosis with prompt surgical excision of primary

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cutaneous melanoma cannot be overemphasized. It remains the most reliable way to cure children of this disease. REFERENCES
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31. Allcutt D, Michowiz S, Weitzman S, et al. Primary leptomeningeal melanoma: an unusually aggressive tumor in childhood. Neurosurgery 1993;32: 721-9. 32. Reed WB, Becker SW Sr, Becker SW Jr, Nickel WR. Giant pigmented nevi, melanoma, and leptomeningeal melanocytosis. Arch Dermatol 1965;91:10019. 33. Tucker MA, Greene MH, Clark WH Jr, Kraemer KH, Fraser MC, Elder DE. Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families. J Pediatr 1983;103:65-9. 34. Greene MH, Clark WH Jr, Tucker MA, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-65. 35. Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions: the B-K mole syndrome. Arch Dermatol 1978;114:732-8. 36. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-50. 37. Greene MH. Dysplastic nevus syndrome. Hosp Pract 1984;19:91-103, 1078. 38. Barker JN, MacDonald DM. Eruptive dysplastic naevi following renal transplantation. Clin Exp Dermatol 1988;13:123-5. 39. Duvic M, Lowe L, Rapini RP, Rodriguez S, Levy ML. Eruptive dysplastic nevi associated with human immunodeciency virus infection. Arch Dermatol 1989;125:397-401. 40. Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol 1992;27:901-13. 41. Smith KJ, Barrett TL, Skelton HG III, Lupton GP, Graham JH. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol 1989;13:931-9. 42. Goldenhersh MA, Savin RC, Barnhill RL, Stenn KS. Malignant blue nevus: case report and literature review. J Am Acad Dermatol 1988;19:712-22. 43. Veronesi U, Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438-41. 44. Ho VC, Sober AJ. Therapy for cutaneous melanoma: an update. J Am Acad Dermatol 1990;22:159-76. 45. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889-97. 46. West WH, Tauer KW, Yannelli JR, et al. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987;316:898-905. 47. Workman ML, Kaye VN, Anderson PM, Cunningham BL. Malignant melanoma with evidence of maturation arising from a giant congenital nevocellular nevus. Ann Plast Surg 1992;28:381-5. 48. Rosenberg SA. Immunotherapy of patients with advanced cancer using interleukin-2 alone or in combination with lymphokine activated killer cells. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Important advances in oncology. Vol. 4. Philadelphia: J.B. Lippincott, 1988:217-57. 49. Idem. Immunotherapy and gene therapy of cancer. Cancer Res 1991;51: Suppl:5074s-5079s. 50. Baas PC, Hoekstra HJ, Schraffordt Koops H, Oosterhuis WJ, van der Weele LT. Hyperthermic isolated regional perfusion in the treatment of extremity melanoma in children and adolescents. Cancer 1989;63:199-203. 51. Phillips GL, Fay JW, Herzig GP, et al. Intensive 1,3-bis(2-chloroethyl)-1nitrosourea (BCNU), NSC:4366650 and cryopreserved autologous marrow transplantation for refractory cancer: a phase I-II study. Cancer 1983;52: 1792-802. 52. Lazarus HM, Herzig RH, Graham-Pole J, et al. Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1983;1:359-67. 53. Boddie AW Jr, Cangir A. Adjuvant and neoadjuvant chemotherapy with dacarbazine in high-risk childhood melanoma. Cancer 1987;60:1720-3. 54. Falkson CI, Falkson G, Falkson HC. Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 1991;9:1403-8. 55. Kirkwood JM, Ernstoff MS, Davis CA, Reiss M, Ferraresi R, Rudnick SA. Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers. Ann Intern Med 1985;103:32-6. 56. McClay EF, Mastrangelo MJ, Berd D, Bellet RE. Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials. Int J Cancer 1992;50:553-6. 57. Hayes FA, Green AA. Malignant melanoma in childhood: clinical course and response to chemotherapy. J Clin Oncol 1984;2:1229-34.

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